Project Summary/Abstract Traumatic Brain Injury (TBI) contributes to a third of injury-related deaths in the US and is among the leading causes of death and disability in people under 35 and over 65. Recent statistics show that TBI annually causes 50,000 deaths, 275,000 hospital admissions, carries an average lifetime expense of $550,000/patient, and an annual economic burden conservatively estimated at $86 billion. The lack of any approved drugs that prevent, minimize, or reverse the brain damage and deficits caused by moderate to severe TBI is a critical unmet need. We propose to test a novel class of vasopressin 1a (V1a) receptor antagonists as a new treatment to meet this need. There is a strong scientific rationale for V1a receptor antagonism as a disease-modifying pharmacotherapy for moderate to severe TBI. Brain edema following TBI is associated with poor prognosis. Following TBI, increased vasopressin (AVP) expression, acting through the V1a receptor, is a major driver of cerebral edema. We recently found that 5 days of treatment with one of Azevan's novel, blood-brain barrier (BBB) penetrating V1a antagonists beginning 24 hr after moderate TBI was induced using the momentum exchange model significantly reduced cerebral edema and eliminated cognitive deficits in concussed animals. The proposed studies will confirm and build on these encouraging preliminary findings. Using the momentum exchange model to induce moderate TBI in female and male rats with a single head strike, four candidate compounds will be screened in physiological, imaging, behavioral, and pharmacokinetic experiments. The compounds will be tested to characterize their effects on 1) edema and resting state functional connectivity using MRI; 2) plasma biomarkers (S100b, GFAP, UCH-l1) in the first 24 hours post-injury that are known to reflect injury severity in rats and humans; and 3) cognitive function based on performance on the Novel Object Recognition task and Barnes Maze test. Finally, we will measure plasma levels of the 4 candidate compounds after intravenous, intraperitoneal, and oral gavage administration. Serial sampling of blood will allow calculation of pharmacokinetic (PK) parameters. These data will help inform planning for studies to help optimize route of administration and formulations for use in treating moderate to severe TBI. The two compounds that most effectively reduce edema, improve rsFC, eliminate cognitive deficits on both tests, and exhibit the best PK profiles (e.g., IV and oral availability, t1/2, AUC) will be designated for continued development in Phase 2, where further IND-enabling work (mechanistic studies, formulation, safety & toxicology) will be undertaken.